Diabetes mellitus is a disease of major global importance, increasing in frequency at almost epidemic rates, such that the worldwide prevalence in 2006 is 170 million people and predicted to at least double over the next 10-15 years. Diabetes is characterized by a chronically raised blood glucose concentration (hyperglycemia), due to a relative or absolute lack of the pancreatic hormone, insulin. Within the healthy pancreas, beta cells, located in the islets of Langerhans, continuously produce and secrete insulin according to the blood glucose levels, maintaining near constant glucose levels in the body.
Much of the burden of the disease to the user and to health care resources is due to the long-term tissue complications, which affect both the small blood vessels (microangiopathy, causing eye, kidney and nerve damage) and the large blood vessels (causing accelerated atherosclerosis, with increased rates of coronary heart disease, peripheral vascular disease and stroke). The Diabetes Control and Complications Trial (DCCT) demonstrated that development and progression of the chronic complications of diabetes are greatly related to the degree of altered glycemia as quantified by determinations of glycohemoglobin (HbAlc). [DCCT Trial, N Engl J Med 1993; 329: 977-986, UKPDS Trial, Lancet 1998; 352: 837-853. BMJ 1998; 317, (7160): 703-13 and the EDIC Trial, N Engl J Med 2005; 353, (25): 2643-53]. Thus, maintaining normoglycemia by frequent glucose measurements and adjustment of insulin delivery is of utmost importance.
Frequent insulin administration can be done by multiple daily injections (MDI) with syringe or by continuous subcutaneous insulin injection (CSII) with insulin pumps. In recent years, ambulatory portable insulin infusion pumps have emerged as a superior alternative to multiple daily injections of insulin. These pumps, which deliver insulin at a continuous basal rate as well as in bolus volumes, were developed to liberate patients from repeated self-administered injections, and allow greater flexibility in dose administration.
Insulin pumps can deliver rapid acting insulin 24 hours a day, for example, through a catheter placed under the skin. The total daily insulin dose can be divided into basal and bolus doses. Basal insulin can be delivered continuously over 24 hours, and can keep the blood glucose levels in normal, desirable range between meals, overnight and during fasting time periods. Diurnal basal rates can be pre-programmed or manually changed according to various daily activities. Insulin bolus doses can be delivered before or after meals to counteract carbohydrates loads or during episodes of high blood glucose concentration levels. For example, the amount of insulin in the administered bolus can depends on several parameters corresponding to a medical state of the patient:                Amount of carbohydrates (Carbs) to be consumed, alternatively defined as “servings”, wherein 1 serving=15 grams of Carbs.        Carbohydrate-to-insulin ratio (CIR), i.e. the amount of carbohydrates balanced by one unit of insulin which is measured in grams per one unit of insulin.        Insulin sensitivity (IS), i.e. the amount of blood glucose lowered by one unit of insulin.        Current blood glucose levels (CBG)        Target blood glucose levels (TBG), i.e. the desired blood glucose levels. TBG for most people with diabetes is in the range of 80-120 mg/dL before a meal, and less than 180 mg/dL 1-2 hours after the beginning of a meal.        Residual insulin (RI), i.e. the amount of stored insulin remained in the body after recent bolus delivery that is still active. This parameter is relevant when there is a short time interval between consecutive bolus doses (e.g. less than 5 hours).        
Although the long term complications of the disease are mainly attributed to hyperglycemic states, hypoglycemia can also pose a major barrier in achieving glycemic targets. For example, it has been shown that asymptomatic nocturnal hypoglycemia can cause clinically important deterioration in glycemic control in patients receiving intensive insulin therapy by causing the Somogyi phenomenon. The Somogyi phenomenon is hyperglycemia induced by a counter-regulatory hormonal response to hypoglycemia (NEJM 1988; 319: 1233-1239.).
Nocturnal hypoglycemia, due to nocturnal hyperinsulinemia, is common in patients with type 1 diabetes and is usually asymptomatic. Nocturnal hyperinsulinemia can occur as a result of the insulin therapy. Although blood glucose levels can often be low during sleep, they are seldom measured routinely. Almost 50% of all episodes of severe hypoglycemia occurs at night during sleep. Such episodes can cause convulsions and coma and have been implicated as a precipitating factor in cardiac arrhythmias resulting in sudden death. Nocturnal hypoglycemia seems to have no immediate detrimental effect on cognitive function; however, on the following day, mood and well-being may be adversely affected. Recurrent exposure to nocturnal hypoglycemia may impair cognitive function; other substantial long-term morbidity includes the development of acquired hypoglycemia syndromes, such as impaired awareness of hypoglycemia (End Practice 2003; 9 (6):530-543).
The risk of hypoglycemia is enhanced by hypoglycemia unawareness and defective glucose counter regulation (e.g. impaired glucagon and attenuated adrenaline responses); conditions that are characteristic of diabetes associated neuropathy (specifically, autonomic sympathetic neuropathy). Hypoglycemia unawareness can occur when a person does not have the early symptoms of low blood glucose. As a result, the person cannot respond in the early stages, and severe signs of hypoglycemia, such as loss of consciousness or seizures, can be more likely.
The combination of hypoglycemia unawareness and defective glucose counter regulation is known as “hypoglycemia associated autonomic failure” (HAAF). A vicious cycle is created since symptomatic hypoglycemia itself reduces sympathetic adrenal response (i.e. adrenaline secretion), which subsequently further increases the unawareness of the succeeding hypoglycemic episode.
It can be concluded that prevention of hypoglycemic episodes, specifically nocturnal hypoglycemic episodes (hereinafter known altogether as “hypoglycemia”), is of utmost importance.
Currently, the strategies used by patients with diabetes for prevention of nocturnal hypoglycemic episodes are inaccurate and based on patient intuition—ingestion of a snack immediately prior to nocturnal sleep (or a fasting time period) containing an arbitrary amount of carbohydrates if blood glucose is low or administration of somewhat smaller amounts of insulin for the night. If the blood glucose is too high, the patient may administer a correction bolus of approximately suitable magnitude.
In view of the foregoing, it would be desirable to provide a device for insulin infusion and a corresponding method to prevent hypoglycemia and achieve better glycemic control, especially during fasting time periods (e.g., overnight sleep).